The present invention relates to stable and highly purified stable hydralazine hydrochloride compositions and stable hydralazine-containing pharmaceutical compositions.
Hydralazine hydrochloride is a peripheral vasodilator that was discovered about 50 years ago. Hydralazine exerts an antihypertensive effect directly on vascular smooth muscle, producing relaxation of muscle fibers resulting in a decrease in blood pressure. Hydralazine is an artery-specific direct peripheral vasodilator having an onset of action between 10-30 minutes (10-20 minutes given intravenously), a maximum hypotensive effect in 10-80 minutes, and duration of action between 3-4 hours. Hydralazine is extensively metabolized in the body to products that are excreted predominantly in the urine, and undergoes N-acetylation, oxidation, hydroxylation, hydrazone formation, and conjugation. Hydralazine is one of the few injectable antihypertensive drugs that maintain blood flow to kidneys during hypertensive crisis, and the only one to increase blood flow to an already compromised kidney.
Over 60 million people in the United States suffer from essential hypertension. About 1% of these people suffers from hypertensive crisis and requires hospital-based acute care. Of the hypertensive crisis patients, 76% are “urgencies” and 24% “emergencies” with end-organ damage. Hypertensive crisis, however, is a medical emergency that requires immediate therapy for certain patients in hospital emergency rooms, operating rooms, and intensive care units. Hypertensive crisis is a life-threatening situation, and includes hypertensive emergencies and hypertensive urgencies characterized by acute elevations in blood pressure that must be brought under control within hours.
A particularly troubling group of patients with hypertensive crisis are women with pregnancy-induced hypertension. Pregnancy induced hypertension complicates 7% to 10% of the estimated 6.2 million pregnancies in the United States each year and is considered a major cause of maternal and fetal morbidity and mortality. These complications vary from mild to severe pre-eclampsia and eclampsia. Severe pre-eclampsia, which occurs in approximately 10% of preeclamptic patients, usually occurs after 20 weeks gestation and is determined by elevated blood pressures of 140/90 mm Hg or greater. It is characterized by hypertension, proteinuria, generalized edema and disturbances in coagulation and liver function. Pre-eclampsia can progress to eclampsia, a convulsive disorder that can cause cerebral hemorrhage and maternal death. Complications resulting from pre-eclampsia and eclampsia are a major cause of maternal deaths around the world, and account for about 17% of maternal deaths in the United States. About half of these deaths in the United States are due to cardiovascular and central nervous system complications, including hemorrhage and embolism. Moreover, in women without proteinuria, the risk of fetal death rises more than three-fold from 6.2/1000 if the diastolic blood pressure is 75-84 mmHg to 19.2/1000 if the diastolic blood pressure is 104 mmHg.
Hydralazine hydrochloride is commercially available in both oral tablet and sterile injectable dosage forms. The sterile injectable form is used to lower blood pressure primarily in pregnant women suffering from severe preeclampsia and eclampsia in hypertensive crisis situations. The oral tablet form of hydralazine hydrochloride is used in patients requiring long-term management of their hypertension after such a crisis has abated. Hydralazine hydrochloride is very unstable in all of the sterile injectable pharmaceutical formulations currently available. Continuing instability problems with injectable hydralazine hydrochloride, for example, have plagued pharmaceutical manufacturers for many years, forcing these companies to remove their injectable hydralazine products from the marketplace. In all current embodiments of its injectable formulations, hydralazine hydrochloride forms small yellow-green particles following storage from 1 to about 2 months when hydralazine is stored at 40° C. and after from 6 to about 9 months storage at 25° C. Although the identification of the yellow-green particles has yet to be confirmed, it is believed that the particles are insoluble polymeric products formed by reaction of hydralazine and contaminating by-products of hydralazine manufacture during storage of hydralazine solutions.
Despite its unique pharmacologic properties as a hypertensive drug, the therapeutic use of hydralazine hydrochloride has been limited by its instability during storage. A stable hydralazine pharmaceutical composition that is more easily manufactured and does not degrade or produce particulate matter during extended storage of the bulk drug substance or its formulations does not currently exist. Moreover, a method of manufacture of hydralazine hydrochloride that provides a pharmaceutical quality product that is free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds is not currently available.
A conventional method of manufacture that is widely used for the commercial manufacture of hydralazine hydrochloride is disclosed in U.S. Pat. No. 2,484,029 to M. Hartmann and J. Druey. According to Hartmann and Druey, hydrazine derivatives of pyridazine compounds are formed by reacting a hydrazine with a pyridazine compound of the desired structure but containing a group in the ortho position to a ring nitrogen that is replaceable by a hydrazine radical. Examples of such replaceable groups are a halogen, an esterified hydroxyl group, or an aryloxy or thioether group. Compounds containing the pyridazine ring that may be used as starting materials are substituted or unsubstituted compounds including 1-chlorophthalazine, 1-chloromethylphthalazine, 1-chloro-4-ethylphthalazine, 1-chloro-4-propylphthalazine, 1-chloro-butylphthalazine, 1-chloro-4-benzylphthalazine, 1-chloro-7-methoxyphthalazine, 1-chloro-7,8-dimethoxyphthalazine, 1-chloro-6-hydroxyphthalazine, 1-chloro-4-phenylphthalazine, 1-chloro-4-(p-methoxyphenyl)phthalazine, 1,4-dichlorophthalazine, 3-chloropyridazine, 3-chloro-6-methylpyridazine, 3-chloro-6-phenylpyridazine, 3-chloro-6-(p-hydroxyphenyl)pyridazine, 6-chloro-3-phenylpyrido-2′,3′,4,5-pyridazine, and 6-chloro-3-phenylpyrido-3′,4′,4,5-pyridazine. Insofar as the starting materials such as the phthalazines or pyridazines are not known, they can be obtained from corresponding oxocarboxylic acids by reaction with hydrazine. The oxo compounds, for example, the phthalazones or pyridazones thus obtained, may be converted into their chlorine compounds, for example, by treatment with phosphorus oxychloride. As hydrazines, hydrazine itself or its substitution products wherein a nitrogen atom may form part of a ring, as, for example, morpholine or piperidine, may be employed. Examples of suitable hydrazines are: hydrazine, methylhydrazine, benzylhydrazine, asymmetrical dimethylhydrazine, symmetrical dimethylhydrazine, propylhydrazine, allylhydrazine, N-methyl-N-butylhydrazine, N-aminopiperidine, N-aminomorpholine, 3-methyl-cyclohexylhydrazine, and the like. Also, these hydrazines may be employed in the form of their salts. The conversion with hydrazines is carried out suitably in the presence of diluents, if desired also in the presence of condensing agents, and if desired in the presence of catalysts such as copper powder.
According to the method of manufacture of U.S. Pat. No. 2,484,029,1-chlorophthalazone is prepared by treating 30 parts by weight of 1-phthalazinone with phosphorus oxychloride as described in Berichte des Deutsche Chemische Gesellschaft, vol. 26, page 521, 1893. The freshly obtained yet moist chloro compound is heated on a water bath for two hours in a mixture of 100 parts by volume of ethyl alcohol and 90 parts by volume of hydrazine hydrate. The hot solution is filtered, and hydralazine crystallizes out in yellow needles on cooling. It is filtered with suction and washed with cold ethyl alcohol. The compound is crystallized from methyl alcohol. On warming in alcoholic or aqueous hydrochloric acid, hydralazine hydrochloride is obtained.
When manufactured according to the methods of manufacture of U.S. Pat. No. 2,484,029, the product, hydralazine hydrochloride bulk solid, is known to contain residuals from the manufacturing process including, for example, hydrazine, chlorinated or chlorophosphorylated phthalazine or pyridazine intermediates, and phthalazone or pyridazone precursors to the chlorophthalazine or chloropyridazine raw material. In addition, if copper powder was employed as a catalyst, the product, hydralazine hydrochloride bulk solid, also contains low concentrations of copper ion (Cu+2).
Because hydrazine is a very toxic chemical, human exposure to hydrazine is severely restricted. Thus, the U.S. Pharmacopeia Official Monograph for hydralazine hydrochloride, for example, requires that pharmaceutical quality hydralazine hydrochloride contain no more than 0.1% hydrazine by weight.
Hydralazine is known to chelate metal ions. Sinha and Motten [Biochemical and Biophysical Research Communications 105(3): 1044-1051 (1982)] report that hydralazine oxidizes rapidly in the presence of oxygen and metal ions such as Cu+2, Fe+2, and Fe+3 through free radical intermediates in a manner similar to other hydrazine derivatives.
When manufactured according to conventional methods of manufacture, hydralazine hydrochloride undergoes degradation during storage to intensely colored, insoluble polymeric products. The numerous degradation products that form during storage have not been completely identified and characterized chemically, but it is believed that they are the products of reactions such as chelation with metal ions, oxidation, reaction of residual hydrazine raw material with chlorinated intermediates that were incompletely removed during manufacturing, and reaction of hydralazine with chlorinated intermediates that were incompletely removed during manufacturing.
It is an object of the present invention to manufacture hydralazine hydrochloride of high pharmaceutical quality that is free of contaminating by-products.
It is an object of the present invention to manufacture hydralazine hydrochloride of high pharmaceutical quality that is free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds.
It is a further object of the present invention to manufacture a stable pharmaceutical formulation of hydralazine hydrochloride that is free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds.
It is a further object of the present invention to manufacture a stable hydralazine hydrochloride pharmaceutical composition that does not degrade or produce particulate matter during extended storage of the bulk drug substance or its liquid formulations.
It is a further object of the present invention to manufacture a stable injectable pharmaceutical formulation containing hydralazine hydrochloride that has no visible particulate matter for a time more than 30 months after manufacture.
It is a further object of the present invention to manufacture a stable injectable pharmaceutical formulation containing hydralazine hydrochloride that has less than 6000 10 micron particles per container or 600 25 micron particles per container for a time more than 30 months after manufacture.
It is a further object of the present invention to produce hydralazine hydrochloride that is stable in sterile injectable pharmaceutical formulations.